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Immunoregulatory Mechanisms of IL-33 in Heart Transplantation

IL-33在心脏移植中的免疫调节机制

基本信息

批准号：
10680570
负责人：
Heth R Turnquist
金额：
$ 61.07万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-10 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680570
关键词：
Alloantigen Allogenic Allografting Antigens Arteries B-Lymphocytes Blood Vessels Brain Death Cause of Death Cell Communication Cells Cessation of life Childhood Chronic Cicatrix Clinical Communication Data Development Disease Resistance Dissection Event Fibroblasts Fibrosis Generations Graft Rejection Growth Factor Heart Transplantation Immune Immune response Immune system Immunoglobulins Immunologics Immunosuppressive Agents Infiltration Inflammation Inflammatory Inflammatory Response Injury Innate Immune System Interferon Type II Interleukin-13 Interleukins Ischemia Life Macrophage Mediating Memory Metabolism Modeling Molecular Mus Myeloid Cells Operative Surgical Procedures Organ Transplantation Pathologic Pathway interactions Pattern Process Production Proliferating Publishing Regulatory T-Lymphocyte Reperfusion Injury Research Resolution Rodent Sampling Secondary to Signal Transduction Stress Stromal Cells T-Cell Proliferation T-Lymphocyte Technology Testing Tissues Transgenic Mice Transplant Recipients Transplantation Trauma Vascular Diseases arginase chemokine cytokine cytotoxicity directed differentiation immunoregulation improved outcome insight isoimmunity monocyte post-transplant pre-clinical prevent promoter receptor repaired response response to injury tissue repair transcriptomics transplant model

项目摘要

Early graft injury is the consequence of unavoidable transplant-associated events, such as donor brain death, ischemia/reperfusion injury, and surgical trauma. Recipient responses to graft alloantigens will also produce graft damage throughout the life of the graft. These injuries and stresses cause the release of self-molecules containing damage-associated molecular patterns (DAMPs). It is well appreciated that DAMPs support pro- inflammatory responses when they are sensed by cells of the innate immune system, particularly monocytes and macrophages. Preclinical rodent heart transplant studies reveal that these released DAMPs initiate and propagate alloresponses and targeting inflammatory DAMPs, or the signaling cascades they activate, reduce alloimmunity and improve outcomes after transplantation. Yet, our recent research has provided compelling evidence that these graft injuries also release reparative DAMPs (rDAMPs), such as Interleukin-33 (IL-33), which limits local inflammation and initiates immune-mediated tissue repair after heart transplant. By assessing pediatric heart transplant recipient samples and using a preclinical mouse heart transplant model, we identified that IL-33 is upregulated in graft stromal cells and limits the development of allograft vasculopathy and graft fibrosis that later culminates in chronic rejection (CR). Our published and preliminary data suggest that IL-33 mediates this protection by targeting infiltrating monocytes and macrophages, as well as regulatory T cells (Tregs), to limit the generation of pro-inflammatory macrophages and then coordinate a Treg and reparative macrophage-mediated response to injury. While these data are encouraging, our studies also suggest that the processes that initiate repair of early tissue damage may become dysregulated over the graft's life. In preliminary data, we show that vessel-associated Tregs become pathologic when their sustained secretion of repair factors in response to IL-33 promotes the proliferation of local fibroblasts contributing to CR. In addition to having their functions programmed by local rDAMPs, graft infiltrating recipient monocytes recognize allogenic molecules causing them to mature into pro-inflammatory myeloid cells that stimulate T cell proliferation and IFNγ production in the graft. We have established that monocytes and macrophages recognize and develop allospecific cytotoxicity and memory to MHCI antigens via paired immunoglobulin-like receptors-A. These data lead us to HYPOTHESIZE that rDAMP signals initiating the repair of tissue damage early after heart transplantation become dysregulated around the vasculature due to a sustained inflammatory response by alloreactive immune cells. We will test this hypothesis in two aims: In AIM 1, we will define how rDAMP and immune cell interactions evolve in heart transplant microenvironments during CR development. In AIM 2, we will establish if innate alloimmunity prevents effective injury resolution and repair after heart transplantation.

早期移植物损伤是不可避免的移植相关事件的结果，例如供体脑死亡、缺血/再灌注损伤和手术创伤。受体对移植物同种异体抗原的反应也会产生移植物损害贯穿移植物的整个生命周期。这些伤害和压力会导致自身分子的释放包含损伤相关分子模式（DAMP）。值得赞赏的是，DAMP 支持亲当先天免疫系统的细胞（特别是单核细胞）感知到炎症反应时和巨噬细胞。临床前啮齿动物心脏移植研究表明，这些释放的 DAMP 启动和传播同种异体反应并靶向炎症 DAMP，或它们激活的信号级联，减少同种免疫并改善移植后的结果。然而，我们最近的研究提供了令人信服的证据有证据表明，这些移植物损伤还会释放修复性 DAMP (rDAMP)，例如白介素 33 (IL-33)，限制局部炎症并在心脏移植后启动免疫介导的组织修复。通过评估儿科心脏移植受者样本并使用临床前小鼠心脏移植模型，我们确定 IL-33 在移植基质细胞中上调并限制同种异体移植血管病变和移植物的发展纤维化，最终导致慢性排斥反应（CR）。我们公布的初步数据表明 IL-33 通过靶向浸润的单核细胞和巨噬细胞以及调节性 T 细胞来介导这种保护 (Treg)，限制促炎性巨噬细胞的产生，然后协调 Treg 和修复性巨噬细胞巨噬细胞介导的损伤反应。虽然这些数据令人鼓舞，但我们的研究还表明在移植物的整个生命周期中，启动早期组织损伤修复的过程可能会变得失调。在初步数据显示，当血管相关调节性T细胞持续分泌修复因子时，它们就会变得病理性 IL-33 的反应可促进局部成纤维细胞的增殖，从而促进 CR。除了拥有他们的由局部 rDAMP 编程的功能，移植物浸润的受体单核细胞识别同种异体分子使它们成熟为促炎性骨髓细胞，刺激 T 细胞增殖和 IFNγ 产生在移植物中。我们已经确定单核细胞和巨噬细胞识别并发育同种异体特异性通过配对免疫球蛋白样受体-A 对 MHCI 抗原产生细胞毒性和记忆。这些数据引导我们假设 rDAMP 信号在心脏移植后早期启动组织损伤的修复由于同种异体免疫的持续炎症反应，脉管系统周围变得失调细胞。我们将在两个目标中检验这一假设：在 AIM 1 中，我们将定义 rDAMP 和免疫细胞如何相互作用 CR 开发期间在心脏移植微环境中进化。在 AIM 2 中，我们将确定是否先天同种免疫可防止心脏移植后损伤的有效消退和修复。